There is evidence that compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as collagenase, stromelysin and gelatinase (known as "matrix metalloproteinases", and herein referred to as MMPs) are potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal, epidermal or gastric ulceration, and tumour metastasis, invasion, and growth.
Metalloproteinases are characterised by the presence in the structure of a zinc(II) ionic site. It is now known that there exists a range of metalloproteinase enzymes that includes fibroblast collagenase (Type 1 ), PMN-collagenase, 72 kDa-gelatinase, 92 kDa-gelatinase, stromelysin, stromelysin-2 and PUMP-1 (J. F. Woessner, FASEB J, 1991,5, 2145-2154). Many known MMP inhibitors are peptide derivatives, based on naturally occuring amino acids, and are analogues of the cleavage site in the collagen molecule. A recent paper by Chapman et al J. Med. Chem. 1993, 36, 4293-4301 reports some general structure/activity findings in a series of N-carboxyalkyl peptides. Other known MMP inhibitors are less peptidic in structure, and may more properly be viewed as pseudopeptides or peptide mimetics. Such compounds usually have a functional group capable of binding to the zinc (II) site in the MMP, and known classes include those in which the zinc binding group is a hydroxamic acid, carboxylic acid, sulphydril, and oxygenated phosphorus (eg phosphinic acid and phosphonic acid) groups.
The following patent publications published prior to the first claimed priority date of this application disclose hydroxamic acid-based MMP inhibitors:
______________________________________ US 4599361 (Searle) EP-A-0231081 (ICI) EP-A-0236872 (Roche) EP-A-0274453 (Bellon) WO 90/05716 (British Bio-technology Ltd ("BBL")) WO 90/05719 (BBL) WO 91/02716 (BBL) WO 92/09563 (Glycomed) EP-A-0497192 (Roche) WO 92/13831 (BBL) EP-A-0489577 (Celltech) EP-A-0489579 (Celltech) WO 92/22523 (Research Corporation Technologies) ______________________________________
The following patent publications published after the first claimed priority date of this application, but before its filing date, also relate to hydroxamic acid-based MMP inhibitors:
______________________________________ US 6256657 (Sterling Winthrop) WO 93/09090 (Yamanouchi) WO 93/09097 (Sankyo) WO 93/20047 (BBL) WO 93/21942 (BBL) WO 93/24449 (Celltech) WO 93/24475 (Celltech) EP-A-0574758 (Roche) WO 94/02446 (BBL) WO 94/02447 (BBL) ______________________________________
The intrinsic potency of compounds within the broad structural groups of hydroxamic derivatives disclosed in the above publications against particular MMPs can be high. For example, many have a collagenase IC.sub.50 by the in vitro test method of Cawston and Barrett, (Anal. Biochem., 99,340-345, 1979) of less than 50 nM. Unfortunately, however, the pharmacokinetic properties of the specific compounds disclosed in those publications have generally been disappointing. Identifying hydroxamic acid-based MMP inhibitors having a good balance of high intrinsic activity and good pharmacokinetic properties, for example prolonged effective plasma concentrations following oral dosing such that the compounds have high in vivo activity in target diseases or conditions such as rheumatoid or osteoarthritis, or cancer, remains a much sought after goal in the art.
With a few exceptions, the hydroxamic acid derivatives disclosed in the above publications can be regarded as having the following basic structure (IA): ##STR1## wherein the five substituents R.sub.1 -R.sub.5 may vary according to the detailed disclosure of each publication. The balance of intrinsic level of activity, degree of specificity of activity for a particular category of MMP, and pharmacokinetic properties can vary in an unpredictable way as the substituents R.sub.1 -R.sub.5 are varied.
Tumour necrosis factor (herein referred to as "TNF") is a cytokine which is produced initially as a cell-associated 28 kD precursor. It is released as an active, 17 kD form, which can mediate a large number of deleterious effects in vivo. When administered to animals or humans it causes inflammation, fever, cardiovascular effects, haemorrhage, coagulation and acute phase responses, similar to those seen during acute infections and shock states. Chronic administration can also cause cachexia and anorexia: Accumulation of excessive TNF can be lethal.
There is considerable evidence from animal model studies that blocking the effects of TNF with specific antibodies can be beneficial in acute infections, shock states, graft versus host reactions and autoimmune disease. TNF is also an autocrine growth factor for some myelomas and lymphomas and can act to inhibit normal haematopoiesis in patients with these tumours.
Compounds which inhibit the production or action of TNF are therefore thought to be potentially useful for the treatment or prophylaxis of many inflammatory, infectious, immunological or malignant diseases. These include, but are not restricted to, septic shock, haemodynamic shock and sepsis syndrome, post ischaemic reperfusion injury, malaria, Crohn's disease, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, rheumatoid arthritis, multiple sclerosis, radiation damage, toxicity following administration of immunosuppressive monoclonal antibodies such as OKT3 or CAMPATH-1 and hyperoxic alveolar injury.
Since excessive TNF production has been noted in several diseases or conditions also characterised by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may have particular advantages in the treatment or prophylaxis of diseases or conditions in which both mechanisms are involved.
Recently, WO 93/20047 disclosed a class of hydroxamic acid based MMP inhibitors which also are active in inhibiting TNF production.